PROGRAM SUMMARY This proposal seeks to renew a successful UCSF Asthma and Allergic Diseases Cooperative Research Center dedicated to identifying molecular phenotypes (endotypes) of asthma and understanding how these endotypes contribute to disease pathophysiology. The proposal builds on our track record of using cell and molecular biology tools, animal models, and human studies focused on the airway epithelium to dissect asthma mechanisms, relate mechanisms to disease phenotypes, predict responses to existing therapies, and identify new therapeutic targets. Work from our Center demonstrated the central importance of direct effects of the type 2 cytokine IL-13 on airway epithelial cells, identified the type 2 asthma endotype as the dominant feature in a large asthma subgroup, established the ability of asthma endotyping to predict therapeutic responses, and showed how IL-13-induced changes in secretory cells cause mucus plugging in fatal asthma. Recent studies from our group and other laboratories implicate other pathways, notably the interferon (IFN) and ER stress pathways, in some individuals with asthma. Despite the considerable progress made by our Center and many others, there is still an urgent need for a more complete understanding of asthma disease mechanisms and more effective therapies for the many individuals with type 2-high or type 2-low asthma who do not respond well to current treatments. This proposal includes two projects that are highly interrelated and share a focus on the epithelium as both a key participant in asthma pathogenesis and a useful sensor for asthma endotyping. Project 1 will determine mechanisms and consequences of heightened epithelial sensitivity to IL-13, examine the basis of IL-13-induced changes in physical properties of mucus that cause airway obstruction, and dissect the contributions of epithelial ER stress in both type 2- and IFN-high asthma. Project 2 will determine the clinical significance of interferon-driven inflammation and airway epithelial ER stress in asthma, establish whether interferon-driven inflammation and airway epithelial ER stress are resistant to and predict poor response to existing asthma therapies, and determine whether specific inhibition of airway epithelial ER stress with a novel therapeutic, KIRA8, improves AHR, inflammation and mucus production in allergic asthma models. A Clinical Subject and Biospecimen Core will recruit and carefully characterize participants with asthma and healthy controls and provide biospecimens that will be used extensively in both projects. An Administrative Core will coordinate Center activities. Through the proposed studies we expect to gain new insights into the mechanistic bases of asthma endotypes and better understand how to target novel pathways important in specific endotypes.